Forces & Cancer From Biology to Physics, from the Laboratory to the Patient Summary CHAPTER 1: THE ADCHIEVMENT Introduction to Physical Oncology (PO) .......................................................... p 3 The Time Scale ................................................................................................. p 7 The Stages of Cancer ........................................................................................ p 7 The Place of the Physical Oncology ................................................................ p 8 An Emerging Science, A Specific Scale .......................................................... p 9 The achievements of PO research .................................................................. p 11 - Cellular rigidity ..................................................................................... p 11 - Cellular / tissue PO: looking for physical parameters .......................... p 11 - The mechanoreceptors ........................................................................... p 12 - The Young's Modulus in vitro ................................................................ p 13 - Ex vivo .................................................................................................... p 14 - Cellular response ................................................................................... p 15 Convergence with Mechanobiology............................................................... p 18 - In vivo ..................................................................................................... p 20 - Feasibility .............................................................................................. p 20 The Constraint Field as a Therapeutic Agent ................................................. p 23 Page 1 sur 42 CHAPTER 2: THE PAST & THE FUTURE The Great Ancestors ....................................................................................... p 24 The war on cancer .......................................................................................... p 25 And Now? ....................................................................................................... p 26 After research will come the development. Today it is necessary to “Let Know” ............................................................. p 27 The continuation of the In Vivo research in the continuity of the Proof of Concept ............................................................................................ p 27 Make available, in the short term, a new treatment for pancreatic cancer; A decisive step for the In Vivo approach ......................... p 29 Beyond Pancreatic Cancer ............................................................................. p 29 What we learned from Mechanobiology in the past ...................................... p 30 Towards a Resonance Frequency? ................................................................. P 30 Towards a Paradigm Considering Mechanical Signals .................................. p 30 A Revisit of Carcinogenesis ........................................................................... p 30 From the Surface of the Cell .......................................................................... p 31 The Stress Field and its Measurement in vivo ............................................... p 32 Fractality of Cancer ........................................................................................ p 33 Cancer metabolism ......................................................................................... p 33 The abbreviations used ................................................................................... p 34 Glossary .......................................................................................................... p 35 References ...................................................................................................... p 41 Page 2 sur 42 CHAPTER 1: THE ADCHIEVMENTS Introduction to Physical Oncology (PO) The study of mechanical signals in oncology has undergone a spectacular revival since the late 1990s. The causes are many: • The exhaustion of the model based on genetics and molecular biology, and the question is cruel when one thinks of disappointed hopes: ‘How many cancer patients have been cured by targeted therapies?’ 1 • The development of cell culture techniques in 3 dimensions (3D), closer to living tissue than 2D cultures. • The inclusion of the extracellular matrix as an essential actor in carcinogenesis and response to treatments. These last two points coincide to impose new models, in vitro or in vivo, to study carcinogenesis and the impact of treatments that take into account what is cancer: 'Solid Tumors' - as opposed to hematological malignant diseases - are organs composed of a tumor tissue itself surrounded by another tissue, the ExtraCellular Matrix (ECM) often called Stroma2. 1 Basically, Chronic Myeloid Leukaemias have not been cured but have seen their lives prolonged for so long that one can equate this with a cure. In "solid tumors", patients with breast cancer treated with adjuvant trastuzumab when the tumor overexpresses HER2, see their percentage of recurrence divided by two. This represents 3% of breast cancers. That's all. In order to be exhaustive, it is necessary to emphasize the minimal part of Targeted Therapies for the "chronicisation" of some cancers such as the breast or the prostate. 2 ECM or stroma, both terms are equivalent. We also find 'Conjunctive Tissue'. Page 3 sur 42 Cancer Cells Normal Cells Diagram showing a tumor invading healthy tissues Figure 1 This pattern shows an 'epithelium' that is the only tissue of cancer origin that we will take into account here and which represents more than 90% of the solid tumors. Normal cells are of Euclidean geometry as well as normal tissue. The medical definition of cancer is the crossing of a barrier, the basal membrane here below. The tumor cells and the tissue they form have a different geometry, fractal, less familiar to our mental representations, hence the description by histologists when they describe cancers of a disorder, anarchy, whereas this geometry is perfectly organized and analyzable. Beneath the basal membrane is the stroma that contains the vessels that will nourish and oxygenate the epithelium. Page 4 sur 42 By reaching this stroma the cancer will quickly constitute an autonomous ECM around him, with his own vessels (neovessels) to nourish and to oxygenate. This tumor vascularization is called neovascularization. Cancer then becomes autonomous, histologically by constituting an 'organ- cancer', and metabolically by developing an energy machinery of its own. In the following we shall consider that the addition of the basement membrane and the stroma below are of the same nature as the ECM, and we shall not distinguish between the two. Metastases are generated by cancer cells that leave the primary tumor and go to different organs to constitute other ‘organs-cancer’ at a distance. Page 5 sur 42 The development of cervical cancer HPV penetrates the epithelium and cavity of the cervix infects the cells of its epithelium base basal membrane stroma if the infection persists, in if the abnormal cells rare cases, abnormal cells proliferate, we speak appear at the base of of pre-cancerous epithelium lesions if the abnormal cells have if the abnormal cells totally invaded, the have crossed the thickness of the basal membrane, we epithelium, we speak of speak of invasive cancer in situ cancer Figure 2 The stages of cancerogenesis in the case of cervical cancer. Progressions of the same type are known in cancers of the colon, bronchus, and in many covering epithelia. Pre-cancerous conditions are also found in many glandular epithelia such as the breast or prostate. Cancer is formed over a long time and is for a long time reversible. The example above shows the very gradual transition over a number of years of a benign anomaly of the cervical epithelium caused by a viral infection (HPV or Page 6 sur 42 Human Papilloma Virus): mild dysplasia. Most often it disappears as well as the next step, severe dysplasia. But the longer the dysplasia persists and increases, the less reversible it is. It can then lead to 'cancer in situ' which is not a cancer in the medical sense (no crossing of the basal membrane) but has all the other characteristics (except the ECM). The Time Scale In response to questions from patients 'but for how long?' Doctors have learned to respond, 'for several years' and ‘for many years’ when the disease follows the most common sequence: dysplasia with or without metaplasia, in situ, primary tumor then metastasis. Let us take the example of the increase in the rigidity of the ECM of a normal epithelium, whether due to inflammation or some other cause. At this slow modification of its environment the cell will respond by a rapid elastic deformation which will accompany the increase of rigidity. Then it will adapt to maintain its architectural integrity by generating an attraction force that will counteract the action of the ECM. This over a longer time. And then one day the geometric distortions will reach a sufficient intensity so that the mitotic spindle until then strictly parallel to the basal membrane ends up exceeding a threshold and lead to asymmetric cell division with loss of polarity. Then the cell divisions will stack cells forming a fractal tissue. The Stages of Cancer For very practical reasons we talk about Stages III to describe cancers that